Dosing regimen for a selective s1p1 receptor agonist

ABSTRACT

The present invention relates to a dosing regimen for a selective S1P 1  receptor agonist, whereby the selective S1P 1  receptor agonist is administered to a subject in such a way that during the initial treatment phase the selective S1P 1  receptor agonist is administered at a dose which induces desensitization of the heart wherein said dose is below the target dose, and at a dosing frequency that sustains desensitization of the heart, until no further acute heart rate reduction occurs, followed by dose up-titration to the target dose of the selective S1P 1  receptor agonist.

FIELD OF THE INVENTION

The present invention relates to a dosing regimen for a selective S1P₁receptor agonist, whereby the selective S1P₁ receptor agonist isadministered to a subject in such a way that during the initialtreatment phase the selective S1P₁ receptor agonist is administered at adose which induces desensitization of the heart wherein said dose isbelow the target dose, and at a dosing frequency that sustainsdesensitization of the heart, until no further acute heart ratereduction occurs, followed by dose up-titration to the target dose ofthe selective S1₁ receptor agonist. The present invention also providesa kit containing different units of medication of a selective S1P₁,receptor agonist for administration according to the invention, wherebyone or more units of a dose strength below the target dose of saidselective S1₁ receptor agonist are provided for the initial treatmentphase, and subsequent units of medication of higher dose strengths up tothe target dose of said selective S1₁ receptor agonist are provided.

BACKGROUND OF THE INVENTION

The present invention provides a dosing regimen for a selective S1₁receptor agonist, by which adverse effects are minimized insubjects/patients during the initial treatment phase, or uponre-initiation of dosing after drug discontinuation.

Selective S1P₁ receptor agonists are compounds which preferentiallyactivate the human

S1P₁ receptor sub-type from among the S1P₁, S1P₂, S1P₃, S1P₄, and S1 P₅family members of sphingosine-l-phosphate-sensitive human G-proteincoupled receptors. S1P receptor agonists decrease the number ofcirculating lymphocytes in peripheral blood in humans or animals aftere.g. oral administration, therefore they have therapeutic potential in avariety of diseases associated with a dysregulated immune system. Forexample, the non-selective S1P receptor agonist FTY720 has been found toreduce the rate of clinical relapses in multiple sclerosis patients(Kappos L et al., N Engl J Med. 2006 Sep 14, 355(11): 1124-40).

However, S1P receptor agonists have been described to reduce heart ratein rodent animal models, an effect that has been attributed to theactivation of the S1P₃ receptor in the sinoatrial nodal tissue of theheart, which increases the I_(K,ACh) inward rectifier current, and slowsthe sinoatrial pacemaker (Hale J J et al., Bioorg Med Chem Left. 2004,14(13): 3501-5; Bünemann Metal., J Physiol 1995, 489: 701-707; Guo J etal., Pflugers Arch 1999, 438: 642-648; Ochi R et al., Cardiovasc Res2006, 70: 88-96). Moreover, the non-selective S1 P receptor agonistFTY720 reduces heart rate in humans (Koyrakh L et al., Am J Transplant2005, 5: 529-536), and the literature suggests that S1P₁ selectivecompounds would have diminished effects on heart rate in humans,compared to non-selective S1P receptor agonists (Himmel H M et al., MolPharmacol 2000, 58: 449-454; Peters S L, Alewijnse A E, Curr OpinPharmacol. 2007, 7(2): 186-92; Fujishiro J et al., Transplantation 2006,82(6): 804-12; Sanna M G et al., J Biol Chem. 2004, 279(14): 13839-48).

DESCRIPTION OF THE INVENTION

The compound (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one(hereinafter also referred to as “Compound 1”; the preparation ofCompound 1 and the medicinal use thereof, is described in the publishedPCT application WO 2005/054215) is a selective S1P₁ receptor agonist,and repeated daily oral dosing of 5 mg or more to humans results in aconsistent, sustained, and dose-dependent reduction in the number ofperipheral blood lymphocytes. It has been surprisingly found, however,that the selective S1P₁ receptor agonist Compound 1 transiently reducesheart rate in humans, with maximal effects 1-3 hours afteradministration. In some individuals this is accompanied by similarlytransient increases in the PR interval in the electrocardiogram (ECG),and an associated irregular heart rhythm (so-called Wenckebach rhythm).Occasional fatigue or dizziness also occur in the post-dose period.These acute effects of Compound 1 on heart rate and rhythm andfatigue/dizziness are milder at 10 mg than at 20 mg. All of theseeffects wane with repeated dosing. Thus, after 2 to 4 days of daily oraldoses of 5 to 20 mg, an acute heart rate reduction, compared to thepre-dose value, is no longer observed upon administration of

Compound 1. Similarly, with repeated daily oral dosing of 5 to 20 mg ofCompound 1, transient increases in the PR interval of the ECG relativeto pre-dose values are not observed, nor are fatigue or dizzinessreported. The acute effects on heart rate, atrioventricular conduction,or fatigue and dizziness, although not seriously adverse, areundesirable, and methods to minimize these effects would be valuable formaximizing the tolerability and safety of Compound 1, and otherselective S1P₁ receptor agonists, and minimizing associated monitoringrequirements, in the early phase of dosing initiation, or, after a druginterruption, at re-initiation of drug therapy.

The subject matter of the present invention therefore provides a dosingregimen for selective S1P₁ receptor agonists, such as and especiallyCompound 1, which minimizes the incidence or severity of the statedadverse effects. The dosing regimen of the present invention providesthat a selective S1P₁ receptor agonist is administered to a subject insuch a way that during the initial treatment phase the selective S1P₁receptor agonist is administered at a dose which induces desensitizationof the heart wherein said dose is below the target dose, and at a dosingfrequency that sustains desensitization of the heart, until no furtheracute heart rate reduction occurs, followed by dose up-titration to thetarget dose of the selective S1P₁ receptor agonist. The dosing regimenof the present invention has the advantage that a desensitization of theheart can be induced and sustained at a dose below the target dose withless pronounced acute heart rate reduction when compared to giving thetarget dose without such a dosing regimen. The dosing regimen of thepresent invention therefore results in an improved tolerability byminimizing the adverse effects in subjects/patients during the firstdays of dosing of a selective S1P₁ receptor agonist, or uponre-initiation of dosing after drug discontinuation.

The choice of the dosing regimen (i.e., the magnitude of the dose andthe dosing frequency) during the initial treatment period can be arrivedat empirically, by comparing the magnitude of the acute heart ratereduction between initial doses given. The dosing frequency should beconvenient for the patient, it should be longer than the duration of theacute heart rate reduction, and it should be shorter than the timerequired for the heart to recover from desensitization. The thusempirically chosen dosing frequency, will reflect the relative rateconstants of several independent processes: the rate constant for theconcentration of the S1P₁ receptor agonist in the body to exceed aconcentration threshold associated with desensitization; the rateconstant for desensitization of the heart; and the rate constant for therecovery from desensitization of the heart. The latter two rateconstants (for desensitization of the heart, and for recovery fromdesensitization) are intrinsic properties of the underlying biologicalprocesses that give rise to these phenomena. The first rate constant(for exceeding the concentration threshold) is determined by thepharmacokinetics of the S1P₁ receptor agonist, i.e., on the rates ofabsorption, distribution, metabolism and excretion of the drug. In viewof the above-mentioned three rate constants, the duration of a suitabledosing interval will be dose-dependent.

For example, Compound 1, when given as a 20-mg once-daily dose by theoral route, results in an acute heart rate reduction on Day 1, and whenthe second 20-mg dose is administered 24 hours later, no acute heartrate reduction is observed. Desensitization has been sustained over this24-hour dosing interval. Yet, when a second 20-mg dose is administered 7days after the first dose, it results in an acute heart rate reductionof similar magnitude as on Day 1. Desensitization has not been sustainedover this 7-day dosing interval of the 20-mg dose. This exampleillustrates that a suitable dosing interval is necessary to sustaindesensitization of the heart.

i) In particular, the present invention relates to a selective S1P₁receptor agonist for use as a medicament, whereby said selective S1P₁receptor agonist is administered to a subject (especially a humansubject) in such a way that during the initial treatment phase theselective S1P₁ receptor agonist is administered at a dose which inducesdesensitization of the heart wherein said dose is below the target dose,and at a dosing frequency that sustains desensitization of the heart,until no further acute heart rate reduction occurs, followed by doseup-titration to the target dose of the selective S1P₁ receptor agonist.

ii) In a further embodiment, the present invention relates to theselective S1 P₁ receptor agonist for use as a medicament according toembodiment i), whereby the initial dose below the target dose is between2- to 5-fold lower than the target dose.

iii) In a further embodiment, the present invention relates to theselective S1P₁ receptor agonist for use as a medicament according toembodiment i), whereby the initial dose below the target dose is between5- to 16-fold lower than the target dose.

iv) In a further embodiment, the present invention relates to theselective S1P₁ receptor agonist for use as a medicament according to anyone of embodiments i) to iii), whereby a dose below the target dose isadministered to the subject during the initial 2 to 4 days of thetreatment.

v) In a further embodiment, the present invention relates to theselective S1P₁ receptor agonist for use as a medicament according to anyone of embodiments i) to iv), whereby the dose below the target dose isadministered at a dosing frequency of once or twice daily.

vi) In a further embodiment, the present invention relates to theselective S1P₁ receptor agonist for use as a medicament according to anyone of embodiments i) to v), wherein the selective S1P₁ receptor agonistis(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,or a pharmaceutically acceptable salt thereof.

vii) In a further embodiment, the present invention relates to the useof a selective S1P₁ receptor agonist in the manufacture of a medicament,whereby said medicament is administered to a subject as specified in anyone of embodiments i) to v).

viii) In a further embodiment, the present invention relates to the useaccording to embodiment vii), wherein the selective S1P₁ receptoragonist is(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,or a pharmaceutically acceptable salt thereof.

ix) The present invention also relates to a kit containing differentunits of medication of a selective S1P₁ receptor agonist foradministration according to embodiment i), whereby one or more units ofa dose strength below the target dose of said selective S1P₁ receptoragonist are provided for the initial treatment phase, and subsequentunits of medication of higher dose strengths up to the target dose ofsaid selective S1P₁ receptor agonist are provided.

x) In a further embodiment, the present invention relates to the kitaccording to embodiment ix), wherein the selective S1P₁ receptor agonistis(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,or a pharmaceutically acceptable salt thereof.

xi) In a further embodiment, the present invention relates to the kitaccording to embodiment ix) or x), whereby subsequent units ofmedication of 2- to 5-fold higher dose strengths compared to the initialdose strength are provided.

xii) In a further embodiment, the present invention relates to the kitaccording to embodiment ix) or x), whereby subsequent units ofmedication of 5- to 16-fold higher dose strengths compared to theinitial dose strength are provided.

xiii) In a further embodiment, the present invention relates to the kitaccording to any one of embodiments ix) to xii), whereby the dosestrength units below the target dose are provided for the initial 2 to 4days of treatment.

xiv) In a further embodiment, the present invention relates to the kitaccording to any one of embodiments ix) to xiii), whereby the dosestrength unit(s) below the target dose is/are administered at a dosingfrequency of once or twice daily.

xv) The present invention further also relates to a method foradministering a selective S1P₁ receptor agonist, whereby the selectiveS1P₁ receptor agonist is administered to a subject as specified in anyone of embodiments i) to v).

xvi) In a further embodiment, the present invention relates to themethod according to embodiment xv), wherein the selective S1P₁ receptoragonist is(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,or a pharmaceutically acceptable salt thereof.

The general terms used hereinbefore and hereinafter preferably have,within this disclosure, the following meanings:

The term “desensitization of the heart” as used herein refers to theabsence of an acute heart rate reduction after drug administration.

The term “acute heart rate reduction” as used herein refers to a heartrate decrease from pre-dose values of, for example, 10 or more beats perminute (bpm), that is maximal within a few hours, for example 1-3 hours,after drug administration, and thereafter the heart rate returns towardsthe pre-dose value.

The term “target dose” as used herein refers to the dose of a selectiveS1P₁ receptor agonist that achieves target peripheral blood lymphocytecounts, e.g., 400-800 lymphocytes per microliter. The target dose for agiven S1P₁ receptor agonist may vary depending on the nature andseverity of the disease to be treated.

Dose up-titration to the target dose can be achieved in one or severaldose increments. For example, a suitable dosing regimen for Compound 1can be 5 mg p.o. (once daily for 3 days; the initial treatment phase),followed by up-titration to 10 mg p.o. (once daily for 3 days), followedby up-titration to 20 mg p.o. (the target dose) given once dailyindefinitely. Another example of a suitable dosing regimen for Compound1 can be 5 mg p.o. (once daily for 3 days; the initial treatment phase),followed by up-titration to 20 mg p.o. (the target dose) given oncedaily indefinitely.

Selective S1P₁ receptor agonists according to the present invention arecompounds which preferentially activate the human S1P₁ receptor sub-typefrom among the S1P₁, S1P₂, S1P₃, S1P₄, and S1P₅ family members,especially compounds which possess a potency for activation of the S1P₁receptor over the other family members of at least 5-fold in a suitableassay. Such suitable assays to determine S1P receptor agonist activitiesare known in the art. In particular, S1P₁ receptor agonist activity of acompound can be tested using the GTPγS assay as described for example inWO 2007/080542 for the human S1P₁ receptor. The same assay can be usedto determine the agonist activities of a compound regarding the otherS1P family members by using CHO cells expressing recombinant human S1P₂,S1P₃, S1P₄, and S1P₅ receptors, respectively.

Preferred selective S1 P₁ receptor agonists according to the presentinvention, their preparation and medicinal use are disclosed in thepublished PCT applications WO 2005/054215, WO 2005/123677, WO2006/010544, WO 2006/100635, WO 2006/100633, WO 2006/100631, WO2006/137019, WO 2007/060626, WO 2007/086001, WO 2007/080542, WO2008/029371, WO 2008/029370, WO 2008/029306, WO 2008/035239, WO2008/114157, and WO 2009/024905.

The selective S1P₁ receptor agonists and their pharmaceuticallyacceptable salts, can be used as a medicament, e.g., in the form ofpharmaceutical compositions for enteral or parenteral administration,and are suitable for the prevention and/or treatment of diseases ordisorders associated with an activated immune system.

The term “pharmaceutically acceptable salts” refers to non-toxic,inorganic or organic acid and/or base addition salts. Reference can bemade to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the selective S1P₁ receptor agonists ortheir pharmaceutically acceptable salts, optionally in combination withother therapeutically valuable substances, into a galenicaladministration form together with suitable, non-toxic, inert,pharmaceutically acceptable solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

Such diseases or disorders associated with an activated immune systemwhich can be treated and/or prevented with selective S1P₁ receptoragonists are described for example in WO 2005/054215.

Preferred diseases or disorders to be treated and/or prevented withselective S1P₁ receptor agonists are selected from the group consistingof rejection of transplanted organs such as kidney, liver, heart, lung,pancreas, cornea, and skin; graft-versus-host diseases brought about bystem cell transplantation; autoimmune syndromes including rheumatoidarthritis, multiple sclerosis, inflammatory bowel diseases such asCrohn's disease and ulcerative colitis, psoriasis, psoriatic arthritis,thyroiditis such as Hashimoto's thyroiditis, and uveo-retinitis; a topicdiseases such as rhinitis, conjunctivitis, and dermatitis; asthma; typeI diabetes; post-infectious autoimmune diseases including rheumaticfever and post-infectious glomerulonephritis; solid cancers; and tumormetastasis.

Particularly preferred diseases or disorders to be treated and/orprevented with selective S1P₁ receptor agonists are selected from thegroup consisting of rejection of transplanted organs selected fromkidney, liver, heart and lung; graft-versus-host diseases brought aboutby stem cell transplantation; autoimmune syndromes selected fromrheumatoid arthritis, multiple sclerosis, psoriasis, psoriaticarthritis, Crohn's disease, and Hashimoto's thyroiditis; and atopicdermatitis. Very preferably the diseases or disorders to be treatedand/or prevented with selective S1P₁ receptor agonists are selected frommultiple sclerosis and psoriasis.

Furthermore, selective S1P₁ receptor agonists are also useful, incombination with one or several immunomodulating agents, for theprevention and/or treatment of the diseases and disorders mentionedherein. According to a preferred embodiment of the invention, saidagents are selected from the group consisting of immunosuppressants,corticosteroids, nonsteroidal anti-infammatory drugs, cytotoxic drugs,adhesion molecule inhibitors, cytokines, cytokine inhibitors, cytokinereceptor antagonists, and recombinant cytokine receptors.

To date, Compound 1 has been administered to humans in three Phase 1studies. In total, 85 subjects have been treated with Compound 1, atsingle doses of up to 75 mg, and at multiple doses of up to 40 mg for upto 15 days.

In the single-ascending dose (SAD) study (AC-058-101), Compound 1 wasadministered orally to 6 groups of 6 healthy male subjects (aged 21-47years). Doses of 1, 3, 8, 20, 50 and 75 mg were given to sequentialgroups of 8 subjects (6 on active drug and 2 on placebo) in arandomized, double-blind, placebo-controlled design. The dose of 20 mgwas given once in the fasted and once in the fed condition, to assessany food effects on the pharmacokinetics of Compound 1. ECGs wererecorded, clinical laboratory parameters, vital signs, pulmonaryfunction, neurological assessments (in the 75-mg dose group), plasmalevels of Compound 1, and peripheral lymphocyte counts (total andsubsets) were determined. All 48 randomized subjects were evaluable andno subjects withdrew or discontinued from the study. All subjectstreated with Compound 1 (n=36) were included in the pharmacokinetic (PK)and pharmacodynamic (PD) analysis.

In Part A of the multiple-ascending dose (MAD) study (AC-058-102),Compound 1 was administered orally with doses of 5, 10, and 20 mgonce-daily for 7 days to healthy male and female subjects (aged 22-58years, 1:1 sex ratio) in a randomized, double-blind, placebo-controlleddesign. At each dose level, a group of 10 subjects were randomized toCompound 1 (8), or placebo (2). In Part A, all 30 randomized subjectscompleted the study and the 24 subjects who were treated with Compound 1were included in the PK analysis.

In Part B of the MAD study, an up-titration scheme was implemented inorder to reduce first-dose effects of Compound 1 on sinus nodeautomaticity and atrioventricular- (AV-) conduction. Treatment withCompound 1 started for 4 days with 10 mg once daily, followed by 4 dayswith 20 mg once daily, and 7 days with 40 mg once daily. Seventeensubjects (nine females and eight males, aged 18-43 years) wererandomized. Thirteen subjects received active treatment and foursubjects received matching placebo. A total of 15 out of the 17 subjectscompleted the study as scheduled. Dosing was discontinued in twosubjects on active treatment due to adverse events, in one case amoderate tooth infection and edema in the mouth, and in the other, amoderate granulocyte shift to the left in the peripheral blood smear,which was already present at baseline. The 11 subjects treated with40-mg Compound 1 who completed the study were included in the PKanalysis of Compound 1.

Table 1 shows the comparison of the mean heart rate (HR) reduction at2.5 h post-dose vs pre-dose in the 40-mg dose group (AC-058-102, Part B)after each titration step (Day 1 for 10 mg, Day 5 for 20 mg, and Day 9for 40 mg) vs HR reduction without up-titration on Day 1 (10 and 20 mgPart A of AC-058-102 and 50 mg of AC-058-101).

TABLE 1 Comparison of the mean HR reduction at 2.5 h post-dose with andwithout up-titration Without up-titration With up-titration Part A MeanHR reduc- Part B Mean HR reduc- (10 and 20-mg) tion (2.5 h post- (40-mgtion (2.5 h post- and 50-mg SAD dose vs baseline) dose group) dose vspre-dose) 10 mg 14 bpm 10 mg 14 bpm  20 mg 22 bpm 20 mg 9 bpm 50 mg 18bpm 40 mg 4 bpm

The mean HR reduction at 2.5 h post-dose vs pre-dose in the 40-mg dosegroup (AC-058-102, Part B) on days 2, 3, and 4 (10 mg) was 2 bpm, 1 bpm,and 1 bpm, respectively, and 4 bpm, 3 bpm, and 3 bpm on days 6, 7, and 8(20 mg), respectively.

During Part B of the study, only one subject reported a transientAV-block first degree after administration of the first 10 mg dose ofCompound 1 on Day 1, suggesting that up-titration reduces the effects ofCompound 1 on both sinus node automaticity and AV-conduction. No secondor third degree AV-blocks were observed during Part B of the study. Norelevant effects on other ECG variables were recorded with multipledosing in Part B.

1. A method for administering a selective S1P₁ receptor agonist or apharmaceutically acceptable salt thereof to a subject in need thereofwherein during an initial treatment phase the selective S1P₁ receptoragonist or pharmaceutically acceptable salt thereof is administered at adose which induces desensitization of the heart to acute heart ratereduction said dose being below the target dose, and at a dosingfrequency that sustains desensitization of the heart, until no furtheracute heart rate reduction occurs, followed by dose up-titration to thetarget dose of the selective S1P₁ receptor agonist or pharmaceuticallyacceptable salt thereof.
 2. The method for administering a selectiveS1P₁ receptor agonist or pharmaceutically acceptable salt thereofaccording to claim 1, wherein the initial dose below the target dose isbetween 2- to 5-fold lower than the target dose.
 3. The method foradministering a selective S1P₁ receptor agonist or pharmaceuticallyacceptable salt thereof according to claim 1, wherein the initial dosebelow the target dose is between 5- to 16-fold lower than the targetdose.
 4. The method for administering a selective S1P₁ receptor agonistor pharmaceutically acceptable salt thereof according to claim 1,wherein the dose below the target dose is administered to the subjectduring the initial 2 to 4 days of the treatment.
 5. The method foradministering a selective S1P₁ receptor agonist or pharmaceuticallyacceptable salt thereof according to claim 1 wherein the dose below thetarget dose is administered at a dosing frequency of once or twicedaily. 6-14. (canceled)
 15. A method of administering to a subject inneed thereof a medication comprising a S1P receptor agonist, wherebysaid S1P receptor modulator or agonist is given at a dosage lower thanthe standard daily dosage of said S1P receptor modulator or agonistduring the initial period of treatment and then the dosage is increased,up to the standard daily dosage of said S1P receptor agonist.
 16. Themethod according to claim 15, wherein the medication is for thetreatment of an autoimmune condition.
 17. The method according to claim16, wherein the autoimmune condition is multiple sclerosis.
 18. Themethod according to claim 15, wherein a sub-therapeutic dose of the S1Preceptor agonist that is 80 fold less, 40 fold less, 10-fold less or4-fold less than the standard daily dosage is administered during theinitial period of treatment.
 19. The method according to claim 15wherein, during the initial period of treatment, the administered dosageis increased stepwise.
 20. The method according to claim 19, wherein theadministered dosage is increased stepwise such that the dosageadministered on a specific day during the initial period of treatment isthe sum of the dosages administered on the previous two days within arange ±40%.
 21. A method for treating a subject in need thereofcomprising administering a S1P receptor agonist which induces a negativechronotropic effect in heart rate, to the subject at a daily dosagewhich is lower than the standard daily therapeutic dosage during aninitial period of treatment and thereafter commencing the administrationof said S1P receptor modulator or agonist at the required standard dailytherapeutic dosage.
 22. The method of claim 21, wherein the patient issuffering from an autoimmune condition.
 23. The method of claim 22wherein the autoimmune condition is multiple sclerosis.
 24. A method ofameliorating or preventing a negative chronotropic side effectassociated with a treatment using an S1P agonist of a subject sufferingfrom an autoimmune disease, comprising administering to the subject inneed thereof, said S1P receptor agonist at a daily dosage which is lowerthan the standard daily dosage during an initial treatment period andraising the daily dosage stepwise up to the standard daily dosage. 25.The method according to claim 21, comprising administering to thesubject, a S1P receptor agonist at a daily dosage which is lower thanthe standard daily dosage during the first 10 days and raising the dailydosage stepwise up to the standard daily dosage.
 26. The methodaccording to claim 24, comprising administering to the subject, a S1Preceptor agonist at a daily dosage which is lower than the standarddaily dosage during the first 10 days and raising the daily dosagestepwise up to the standard daily dosage.
 27. A method of administeringto a subject in need thereof a medication comprising a S1P₁ receptoragonist, whereby said S1P₁ receptor modulator or agonist is given at adosage lower than the standard daily dosage of said S1P₁ receptormodulator or agonist during the initial period of treatment and then thedosage is increased, up to the standard daily dosage of said S1P₁receptor agonist.
 28. The method according to claim 27, wherein themedication is for the treatment of an autoimmune condition.
 29. Themethod according to claim 28, wherein the autoimmune condition ismultiple sclerosis.
 30. The method according to claim 27, wherein asub-therapeutic dose of the S1P₁ receptor agonist that is 80 fold less,40 fold less, 10-fold less or 4-fold less than the standard daily dosageis administered during the initial period of treatment.
 31. The methodaccording to claim 27, wherein, during the initial period of treatment,the administered dosage is increased stepwise.
 32. The method accordingto claim 31, wherein the administered dosage is increased stepwise suchthat the dosage administered on a specific day during the initial periodof treatment is the sum of the dosages administered on the previous twodays within a range ±40%.
 33. A method for treating a subject in needthereof comprising administering a S1P₁ receptor agonist which induces anegative chronotropic effect in heart rate, to the subject at a dailydosage which is lower than the standard daily therapeutic dosage duringan initial period of treatment and thereafter commencing theadministration of said S1P₁ receptor modulator or agonist at therequired standard daily therapeutic dosage.
 34. The method of claim 33,wherein the patient is suffering from an autoimmune condition.
 35. Themethod of claim 34 wherein the autoimmune condition is multiplesclerosis.
 36. A method of ameliorating or preventing a negativechronotropic side effect associated with a treatment using an S1P₁agonist of a subject suffering from an autoimmune disease, comprisingadministering to the subject in need thereof, said S1P₁ receptor agonistat a daily dosage which is lower than the standard daily dosage duringan initial treatment period and raising the daily dosage stepwise up tothe standard daily dosage.
 37. The method according to claim 33,comprising administering to the subject, a S1P₁ receptor agonist at adaily dosage which is lower than the standard daily dosage during thefirst 10 days and raising the daily dosage stepwise up to the standarddaily dosage.
 38. The method according to claim 36, comprisingadministering to the subject, a S1P₁ receptor agonist at a daily dosagewhich is lower than the standard daily dosage during the first 10 daysand raising the daily dosage stepwise up to the standard daily dosage.